: This application for a NIDA Senior Scientist Award (K05) requests support for the candidate to pursue a multidisciplinary program focused on drug abuse research. The candidate's overall objectives are to investigate the molecular targets of psychostimulant drugs of abuse, the neuroadaptive mechanisms consequent to chronic drug exposure and to develop novel and effective medications for cocaine addiction. The dopamine transporter, a principal target of cocaine and amphetamine, is the major focus of the research. The research program is based on exciting leads generated over the previous project period and is supported by two grants from NIDA and two subcontracts. An ongoing objective is to investigate the therapeutic potential of novel cocaine agonists targeted to the dopamine transporter, with molecular, biochemical, behavioral and brain imaging techniques. Non-amines, and "tropane horses" are a major focus of the medications development research. Non-amines bear no amine nitrogen in their structure yet retain the high affinity for the monoamine transporters and appropriate brain distribution, of their amine progenitors. "Tropane horses" are a new class of compounds designed as cocaine antagonists. PET imaging of brain dopamine transporters will monitor dopamine transporter occupancy of candidate medications to establish drug doses that fully block access of cocaine to the transporter. Cell and molecular biology approaches will provide a mechanistic platform in support of our research. We will investigate the relevance of dopamine transporter gene polymorphisms to behavioral responses elicited by psychostimulants and the influence of polymorphisms on dopamine transporter density. Substrate or inhibitor induction of immediate early gene expression in cells transfected with the dopamine transporter will guide parallel investigation of neuroadaptive processes in pre-synaptic dopamine neurons. The research will be conducted in cell lines transfected with primate transporters and in non-human primates. This integrated research program will provide fundamental information on the neurobiological mechanisms underlying the behavioral effects of psychostimulants and candidate medications to treat cocaine addiction.